Grand Rounds: Purines, Alcohol, and Fatty Liver Disease

April 8, 2009

Commentary by Peter Shue MD, PGY-3

The medical grand rounds presentation on March 4, 2009 was delivered by a distinguished NYU faculty member and research investigator, Dr. Bruce Cronstein. Although his training and research is primarily in rheumatology, he breathed new insight into mechanisms of fatty liver disease. In his talk, he reviewed his own published experiments showing that fatty liver disease, similar to gout, is potentiated by elevations in adenosine. In gout, excess adenosine is ultimately metabolized to uric acid which is then deposited into joint spaces, causing inflammation. However, the development of fatty liver disease is mediated by cell signaling from adenosine and its receptors. He showed that excess ethanol ingestion or high fructose consumption increases adenosine levels within hepatocytes and can result in fatty liver disease.

Dr. Cronstein began his talk by introducing adenosine as an endogenous purine nucleoside which plays an important role in cellular metabolism. It is the basic substrate for the production of ATP, which is the chemical fuel for virtually all metabolic processes in the cell. Cellular stresses such as hypoxia, exposure to oxygen free radicals, direct injury and certain toxins, upregulate production of adenosine. This ultimately increases production of ATP, which alters cellular metabolism to react to the stress. Besides being a substrate for ATP production, adenosine has an important role in signal transduction. The adenosine receptor includes several subtypes: A1, A2A, A2B, and A3. They are all seven transmembrane G-protein coupled receptors. These receptors are found in multiple cell types and have a wide range of function.

The A1 receptor is responsible for AV nodal blockade and endothelial dependent vasodilation. Adminstration of intravenous adenosine has been used to terminate certain supraventricular tachycardias that require the AV node for re-entry. The A2A receptor appears to mediate an anti-inflammatory effect and is important in wound healing. The A2B receptor induces mass cell degranulation and bronchospasm. The A3 receptor currently has an unknown function. Whereas the A1,A2A,A2B receptors are well conserved among different species, the A3 is the only adenosine receptor that is poorly conserved. This makes it difficult to elucidate its function in animal models.

Heavy ethanol ingestion has been well described to result in the development of fatty liver disease. The pathophysiology is not well understood, but recent studies suggest that adenosine and its receptors may play a role in the progression of hepatic steatosis. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase, which is further metabolized to acetate by aldehyde dehydrogenase. Acetate is subsequently metabolized to acetyl-CoA, which generate adenosine from the catabolism of ATP to ADP. Ethanol is also well known to stimulate increased extracellular adenosine concentration in vitro through its action on the nucleoside transporter.

Dr. Cronstein reviewed his own experimental data that was recently published in the Journal of Clinical Investigation.In his elegant mice experiments, he demonstrated that ethanol-induced hepatic steatosis is mediated by the A1 and A2B adenosine receptors by two distinct signaling pathways in hepatocytes. The A1 receptor upregulates expression of transcription factors, SREBP1 and PPARg. The end result is the upregulation of lipogenesis in the hepatocyte. The A2B adenosine receptor activates PPARa and AMP-activated kinase that downregulate fatty oxidation and reduce ultilization of lipid stores in the hepatocyte. In animal knock-out models, mice that lack either the A1 or A2B adenosine receptor have significantly diminished fatty liver changes as compared to wildtype mice when fed ethanol. These differences were reproduced in wildtype mice that were given A1 or A2B receptor antagonists.

Non-alcoholic fatty liver disease (NAFLD) is an increasing prevalent disease process in the United States and may lead to cirrhosis. It is often associated with metabolic syndrome and/or obesity. Similar to ethanol-induced hepatic steatosis, NAFLD may also be mediated by adenosine and its receptors. High fructose ingestion is associated with NAFLD and epidemical data reveals a strong correlation in the rising incidence of NAFLD and fructose consumption (high fructose corn-syrup being an ingredient in many processed foods). Mice fed a high fructose diet develop NAFLD, which further supports this association. The mechanism may be due to the excess generation of adenosine during the metabolism of fructose. A1 adenosine receptor knock-out mice have significantly reduced fatty liver changes when compare to wildtype mice that are fed a high fructose diet.

Dr. Cronstein concluded his talk with a discussion of caffeine, a weak non-selective adenosine receptor antagonist, and its ability to reduce fatty liver changes in mice. In human epidemiological studies, Dr. Arthur Klatsky and colleagues at the Kaiser Permanente Medical Care Program studied more than 125,000 people over a 20-year period and found that drinking coffee reduced the risk of cirrhosis, particularly from alcoholic cirrhosis.

Dr. Bruce Cronstein presented an insightful grand rounds lecture on the key role of adenosine and its receptors in the development of fatty liver disease, both in alcohol and non-alcohol induced. Agents that block this pathway may have great clinical application in the future.

Trip Database

Meta

Subscribe to receive new articles

Leave Blank:Do Not Change:

Your email:

Comments and questions? Please contact Us.
Copyright New York University
All rights reserved. Electronic ISSN 1944-0030.
The content of this site is intended for health care professionals.
clinicalcorrelations.org is in the cloud